Process for the preparation of thiazole derivatives

ABSTRACT

The present invention relates to intermediate thiazole compounds and a process for preparing 2-chloro-5-chloromethylthiazole which is a known compound useful for the preparation of insecticides.

This application is a division of Ser. No. 10/049,073 filed Feb. 4,2002, now U.S. Pat. No. 6,476,230, which is a 371 of PCT/EP00/07709filed Aug. 8, 2000, and a division of Ser. No. 09/371,180, filed Oct. 8,1999, now U.S. Pat. No. 6,265,553.

FIELD OF THE INVENTION

The present invention relates to intermediate thiazole compounds and aprocess for preparing 2-chloro-5-chloromethyl-thiazole which is a knowncompound useful for the preparation of insecticides.

BACKGROUND OF THE INVENTION

The compound 2-chloro-5-chloromethyl-thiazole is known intermediateuseful for the preparation of insecticides. See European patentapplication No. 192,060. U.S. Pat. No. 4,748,243 to Beck et al. and EP448,913 describe a process of preparing 2-chloro-5-chloromethyl-thiazoleby reaction certain allyl isocyanates with chlorine.

SUMMARY OF THE INVENTION

Surprisingly, it has now been discovered that2-chloro-5-chloromethylthiazole may be conveniently prepared from2-chloro-5-hydroxymethylthiazole, 2-hydroxy-5-hydroxymethylthiazole or a5-hydroxymethylthiazol-2-diazonium salt compound. These processes avoidthe costs and hazards of using allyl isocyanate reagents and chlorine.Additionally, it has been discovered that2-chloro-5-hydroxymethylthiazole and 2-hydroxy-5-hydroxymethylthiazolemay be prepared via a 5-hydroxymethylthiazol-2-diazonium intermediate.Surprisingly, it has also been discovered that the2-chloro-5-hydroxymethylthiazole, the 2-hydroxy-5-hydroxymethylthiazoleor the 5-hydroxymethylthiazol-2-diazonium salts may be derived from2-amino-5-hydroxymethylthiazole which is a known compound.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the invention is the compound2-hydroxy-5-hydroxymethyl-thiazole having the formula:

(and acid addition salts thereof) which is also useful for making2-chloro-5-chloromethylthiazole.

It is recognized that salts 2-hydroxy-5-hydroxymethylthiazole are alsosimilarly useful intermediates and are part of the instantly disclosedinvention. For example, the hydrochloride salts of2-chloro-5-hydroxymethylthiazole and 2-hydroxy5-hydroxy-methylthiazolealso are useful intermediates for preparing 2-chloro-5-chloromethylthiazole.

Another embodiment of the invention is5-hydroxymethylthiazolyl-2-diazonium salt of formula:

(and acid addition salts thereof) wherein A⁻ is a counter-anion derivedfrom an acid HA, wherein HA is an organic acid or inorganic mineralacid. The organic acid for example may be formic acid, acetic acid, orbenzoic acid. The inorganic acid for example may be a halogen acid,sulfuric acid, nitric acid, or phosphoric acid. Preferably A⁻ is ahalogen anion, an anion of the formula ⁻OSO₂R₁ wherein R₁ is C₁-C₄alkyl, phenyl, C₇-C₁₀alkylaryl, or C₅-C₁₀cycloalkyl; or an anion of theformula ⁻OOC—R₂ wherein R₂ is C₁-C₄-haloalkyl or R₁. The diazonium saltsare useful for making 2-chloro-5-hydroxymethylthiazole,2-hydroxy-5-hydroxymethylthiazole and 2-chloro-5-chloromethylthiazole.

Another embodiment of the invention is the process for making2-chloro-5-chloromethylthiazole (and acid addition salts thereof)comprising the step of reacting the known2-chloro-5-hydroxymethylthiazole, or 2-hydroxy-5-hydroxymethylthiazoleor a 5-hydroxymethylthiazolyl-2-diazonium salt with a chloride anionsource in the presence of an acid. The chloride anion source is notlimited to but may be selected from the group consisting of an inorganicacid, a chloride salt, an acyl chloride and a sulfonyl chloride. Theinorganic acid acting as the chloride anion source for example may beHCl, SOCl₂, PCl₃, POCl₃, or PCl₅. The chloride salt may be for exampleNaCl, KCl, CaCl₂, ammonium chloride or a mono-, di-, tri-,tetra-alkylammonium chloride. The acyl chloride for example may beacetyl chloride or benzoyl chloride; or for example a chloroformate or athiochloroformate such as ethyl chloroformate or ethylthiochloroformate. The sulfonyl chloride for example may be mesylchloride or tosyl chloride. It will be recognized that when the startingreagent is a hydrochloride addition salt or is5-hydroxymethylthiazolyl-2-diazonium chloride salt, the starting reagentitself will serve also as a chloride anion source.

The skilled artisan will realize that the presence of acid in thereaction medium may be generated in situ from the reaction of theappropriate chloride anion source with the2-chloro-5-hydroxymethylthiazole, 2-hydroxy-5-hydroxymethylthiazole orany hydroxylic solvent that may be present in the reaction medium. Thepresence of acid in the reaction medium may also be provided by theaddition of an organic acid or an inorganic acid. The organic acid forexample may be formic acid, acetic acid, or benzoic acid. The inorganicacid for example may be a halogen acid, sulfuric acid, nitric acid,sulfur trioxide, phosphoric acid or phosphorous pentoxide.

The process may preferably be conducted in the presence of a solvent.The solvent for example may be hexane, cyclohexane, chloroform,methylene chloride, diethyl ether, tetrahydrofuran, toluene, or water,or mixtures thereof. When water is present other by-products may resultdue to the hydrolysis. The process may also be advantageously conductedunder reflux conditions.

Another embodiment of the invention is the process for making2-chloro-5-hydroxymethylthiazole (and acid addition salts thereof)comprising the step of reacting 2-amino-5-hydroxymethylthiazole (andacid addition salts thereof) with an alkali metal nitrite in thepresence of an acid and in the presence of a chloride anion source. Thealkali metal nitrite may be either sodium nitrite or potassium nitrite.The presence of a chloride anion source may be obtained by addition ofthe chloride anion source described above. The presence of acid in thereaction medium may be achieved in a similar fashion as discussed abovefor preparing 2-chloro-5-chloromethylthiazole. Thus it will berecognized that under the appropriate reaction conditions (e.g.temperature, pressure, concentration, reaction time etc.),2-chloro-5-chloromethylthiazole may be prepared directly from2-amino-5-hydroxymethylthiazole without isolating or purifying theintermediate 2-chloro-5-hydroxymethylthiazole.

Another embodiment of the invention is the process for making2-chloro-5-hydroxymethylthiazole (and acid addition salts thereof)comprising the step of reacting a 5-hydroxymethylthiazolyl-2-diazoniumsalt with a chloride anion source in the presence of an acid. Thereaction conditions regarding the chloride anion source and the presenceof acid are the same or similar to those used for the preparation of2-chloro-5-chloromethylthiazole discussed above. It will be recognizedthat when the 5-hydroxymethylthiazolyl-2-diazonium chloride salt (orhydrochloride salt thereof) is used it will serve also as a chlorideanion source.

Another embodiment of the invention is the process for making2-hydroxy-5-hydroxymethylthiazole (and acid addition salts thereof)comprising the step of reacting 2-amino-5-hydroxymethylthiazole (andacid addition salts thereof) with an alkali metal nitrite in thepresence of water. The alkali metal nitrite may be either sodium nitriteor potassium nitrite. The presence of a water may be obtained byaddition of water or the water may be carried into the reaction from theprevious reaction step(s) for preparing the2-amino-5-hydroxymethylthiazole. Thus it will be recognized that thefurther addition of a chloride anion source in the presence of acid maybe used to prepare 2-chloro-5-chloromethylthiazole directly from2-amino-5-hydroxymethylthiazole without isolating or purifying theintermediate 2-hydroxy-5-hydroxymethylthiazole.

Another embodiment of the invention is the process for making2-hydroxy-5-hydroxymethylthiazole (and acid addition salts thereof)comprising the step of reacting a 5-hydroxymethylthiazolyl-2-diazoniumsalt with water.

Another embodiment of the invention is the process for making the5-hydroxymethylthiazolyl-2-diazonium salt of formula (1) (and acidaddition salts thereof) comprising the step of reacting2-amino-5-hydroxymethylthiazole with an alkali metal nitrite in thepresence of acid. The alkali metal nitrite may be either sodium nitriteor potassium nitrite. The presence of acid in the reaction medium may beachieved in a similar fashion as discussed above for preparing2-chloro-5-chloromethylthiazole. Thus it will be appreciated that by thefurther addition of a chloride anion source and with other appropriatereaction conditions (e.g. temperature, pressure, concentration, reactiontime etc.), 2-chloro-5-chloromethylthiazole may be prepared directlyfrom 2-amino-5-hydroxymethylthiazole without isolating or purifying theintermediate a 5-hydroxymethylthiazolyl-2-diazonium salt. It will berecognized that the 5-hydroxymethylthiazolyl-2-diazonium chloride salt(or hydrochloride salt thereof) may serve also as a chloride anionsource.

Another aspect of the invention is the product produced from the processof diazotizing 2-amino-5-hydroxythiazole (and addition salts thereof)with aqueous alkali metal nitrite. The5-hydroxymethylthiazolyl-2-diazonium salt of formula (1) or the productfrom the process of diazotization (to the extent there is a difference)are both features of the instantly disclosed invention. The scope of theinvention as to the diazonium salts and the process of preparing thecompound of formula (1) disclosed herein should not be construed to belimited by any particular chemical theory relating to the complexation,equilibration, reaction or acid-base chemistry of the components used tomake the diazonium salt or the final product. Another aspect of theinvention is a 5-hydroxymethylthiazolyl-2-diazonium salt of formula (1)wherein said salt has interacted chemically so as to result in a changedform of the salt or has interacted with other chemical components so asto form another more stable compound or acid addition salt thereof.Accordingly, the present invention encompasses the substantiallyunaltered static composition of the appropriate components as well asthe chemically integrated composition. “Static composition” denotes 1)the composition composed of components wherein the components have notsubstantially changed by virtue of their combination or interaction withother composition components, or 2) the composition that has reacted toa point of relative stasis. “Chemically integrated composition” means acomposition that results from any equilibration, complexation,dissociation or other chemical transformation (if any) that may occurafter combination of the reagents used to prepare the productcomposition containing the salts of formula (1) and prior to ultimateuse for the preparation of 2-chloro-5-hydroxymethylthiazole,2-chloro-5-chloromethylthiazole and 2-hydroxy-5-hydroxymethylthiazole.Therefore, the “chemically integrated composition” of the instantinvention by definition encompasses the situation where there is anunchanged “static composition” as well as the equilibrated orsemi-equilibrated composition existing at any point between initialcreation and ultimate use. In other words, the disclosed inventionrelating to diazonium salts is not limited to a static composition ofchemically unaltered constituent components.

Another embodiment of the invention is the process for making2-amino-5-hydroxymethylthiazole (and acid addition salts thereof)comprising the step of reacting epoxypropanal with thiourea, preferablyin an aqueous solvent system. The epoxypropanal is a known compound andmay be prepared for example by reacting acrolein with an epoxidizingagent, preferably in an aqueous solvent system. The peroxides that aresuitable epoxidizing agents are known and include hydrogen peroxide,alkylhydroperoxides, dialkylperoxides, peracids and peracid anhydrides.Examples of peracids include peracetic acid and perbenzoic acid.

Another aspect of the instant invention is the preparation of2-amino-5-hydroxythiazole directly from acrolein by reaction with aperoxide followed by reaction with thiourea, without isolating orpurifying the intermediate epoxypropanal. The reaction is preferablyconducted under aqueous solvent conditions.

By “addition salts” are meant salts of a given compound (or salt) of theinvention derived from the chemical interaction with inorganic acids ororganic acids. Acid addition salts may also be adducts with an organicsolvent or water.

Examples of acid addition salts derived from inorganic acids includehydrochlorides hydrobromides, hydroiodides, sulfates, hydrogensulfates,phosphates, monohydrogenphosphates, dihydrogenphosphates, nitrates, andthiocyanates. Examples of acid addition salts derived from organic acidsinclude carboxylates, sulfonates, and phosphonates. Examples of acidaddition salts derived from a carboxylic acid include formates,acetates, propionates, butyrates, cinnamates, benzoates, lactates,oxalates, malonates, succinates, glutarates, adipates, maleates,fumarates, phthalates, citrates, tartarates, salicylates, nicotinates,mandelates and salts from amino acids. Examples of acid addition saltsderived from a sulfonic acid include alkylsulfonates (e.g.methanesulfonates, benzenesulfonates (e.g. p-toluenesulfonates),naphthlenesulfonates and camphorsulfonates. Examples of acid additionsalts derived from a phosphonic acid include alkylphosphonates (e.g.methylphosphonates) and benzenephosphonates (e.g. phenylphosphonates).

By “alkyl” is meant a C₁-C₁₀ alkyl group which is linear or branched.Examples of suitable alkyl groups include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, neo-pentyl,n-hexyl, n-octyl and n-decyl.

Scheme I (below) provides an additional description of some of theembodiments of the invention and their interrelationship.

The following examples illustrate further some of the specific featuresof the invention but are not intended to limit its scope. Where nototherwise specified throughout this specification and claims,temperatures are given in degrees centigrade.

EXAMPLE 1 Preparation of Epoxypropanal

A solution of 800 ml water and 118 g. of 30% hydrogen peroxide (1.04mole) was adjusted to a pH of 8.0-8.5 and cooled to 10° C. Whilemaintaining a pH of 8-8.5 and a temperature of 10-20° C., 56 g (1.00mole) of acrolein is added dropwise. The aqueous solution of the epoxypropanal must be kept cold until it is used directly to make2-amino-5-hydroxymethylthiazole. The product may also be isolated usingknown procedures.

EXAMPLE 2 Preparation of 2-amino-5-hydroxymethylthiazole

The epoxy propanal solution from example 1 is cooled to 0° C. Withvigorous stirring, 76 g (1.00 mole) of thiourea was added in portions.After the addition is complete the water is removed under vacuum on arotatory evaporator. An oil is isolated as the product (91.3 g).

EXAMPLE 3 Preparation of 5-hydroxymethylthiazole-2-diazonium chloridesalt

A reactor vessel is charged with 2-amino-2-hydroxymethylthiazole (1.0moles, in a concentrated hydrochloric acid solution). The solution iscooled to 0° C. and sodium nitrite (1.1 equiv., in a concentratedhydrochloric acid solution) is added drop-wise to the reactor vesselwith vigorous agitation of the reaction while maintaining thetemperature in the range 0° C. to 20° C. After the addition is completethe reaction medium is maintained at 0° C. with stirring for 3 hours.Excess nitrous acid is then quenched by addition of urea. The product5-hydroxymethylthiazole-2-diazonium salt may be isolated using knownextraction and solvent removal procedures or the reaction product may beused directly to prepare 2-chloro-5-hydroxylmethylthiazole,2-hydroxy-5-hydroxylmethylthiazole or 2-chloro-5-chloromethylthiazole.

EXAMPLE 4 Preparation of 2-chloro-5-hydroxylmethylthiazole

One liter of the aqueous solution from example 2 (containingapproximately 0.6 moles of amino-hydroxymethylthiazole) was mixed with35 ml. of concentrated hydrochloric acid to achieve a pH of 3. Thesolution was chilled to 0° C., and sodium nitrite (30 g, 0.45 moles) wasadded in portions. The solution was maintained at 0° C. while anadditional 15 ml. of concentrated hydrochloric acid was added dropwise.Cuprous chloride (35 g) was added, and the mixture was heated to 48° C.for 1 hour. Upon cooling, the solution was filtered. Acetic anhydride(100 g) and urea (10 g) were added. The solution was extracted withbutanol. Butanol extract furnished 2-chloro-5-hydroxylmethylthiazole.

EXAMPLE 5 Preparation of 2-chloro-5-chloromethylthiazole

A 1.00 mole batch of 2-amino-5-hydroxymethylthiazole was prepared inwater as described above in Example 2. The water was removed by rotoryevaporation, and the residue was dissolved in 500 ml. of concentratedHCl. The solution was cooled to between −5 and 5° C., then 1.00 mole ofsodium nitrite was added in portions. The temperature of the reactionsolution increased to 11° C. after an exotherm. The solution was thenallowed to stir for 2 hours. Twenty grams of urea was added, followed by50 ml of concentrated nitric acid. The solution was cooled to 0° C. and8 g of copper metal was added and the solution was stirred overnight.The mixture was extracted 3 times with methybutylketone. The solvent wasremoved by rotary evaporation to yield an oil (18 g.) that wasidentified by GC MS as 2-chloro-5-chloromethylthiazole.

In summary, it is seen that this invention provides new intermediatesthat are useful for preparing the 2-chloro-5-chloromethylthiazole whichis an intermediate that is known to be useful for preparinginsecticides. The invention also encompasses the processes for makingthe intermediates used to make 2-chloro-5-chloromethylthiazole.Variations may be made in proportions, procedures and materials withoutdeparting from the scope of the invention as defined by the followingclaims.

What is claimed is:
 1. A process for preparing the compound having theformula:

and acid addition salts thereof, comprising the step of reacting2-hydroxy-5-hydroxymethylthiazole having the formula:

with a chloride anion source in the presence of an acid.